The brain is dependent on a continuous blood flow for supply of substrates and oxygen. Cerebral blood flow (CBF) is the most important factor for maintenance of brain metabolism. Different mechanisms regulate CBF (e.g. coupling, autoregulation) . As CBF is essential in neuroanaesthesia, various anaesthesia techniques and drugs that might influence CBF are investigated. Although cerebral blood flow velocity (CBFv) in the middle cerebral artery is no direct measurement of CBF, changes in CBFv reliably correlate with changes in CBF in the presence of a constant vessel diameter [2, 3, 4].
Effects of volatile anaesthetics on CBFv are well documented [1,5, 6, 7, 8]. In addition, effects of volatile anaesthetics on the cardiovascular system have been investigated . The relationship between cardiac output and CBF is controversially discussed [10, 11, 12]. Intact vs. impaired cerebral autoregulation in correlation with changes in mean arterial pressure (MAP) are discussed in these articles. Because neither cardiac output nor mean arterial pressure were reliable parameters for a correlation with cerebral blood flow, we studied CBFv and systemic blood flow velocity (blood flow velocity in the aorta) (SBFv). Considering only the absolute CBFv could lead to misinterpretation of cerebral changes in blood flow, because part of these changes could be caused by changes in systemic blood flow (SBF). However, it has not been investigated whether the relative changes in CBFv are the result of relative changes in SBFv. In the presence of the same heart rate and a constant vessel diameter, SBFv and CBFv are comparable variables on one line of flow transmission.
The aim of our study was to evaluate whether the effects of isoflurane and sevoflurane on CBFv are independent of relative changes in SBFv.
The protocol of this prospective, randomized, doubleblind study was approved by the local Ethics Committee. After written informed consent, 40 patients (ASA I-III) requiring general anaesthesia undergoing routine spinal surgery were randomly assigned to either isoflurane (group 1) or sevoflurane (group 2). The age of the patients was similar in both groups (group 1: 24-62 years; group 2: 24-61 years). Patients with either cerebral or cardiovascular diseases were excluded from the study.
Patients' vital signs (heart rate, arterial pressure, SPO2 determined by pulse oximetry, and body temperature) were monitored continuously (Merlin monitor, Hewlett Packard, Pala Alto, CA, USA). Arterial pressure prior to induction of anaesthesia was measured noninvasively, and when the patient had been anaesthetized an arterial catheter in the radial artery and a urinary catheter were routinely placed. The urinary catheter was also used to measure body temperature . Body temperature was maintained applying body surface warming using a Bair Hugger (Augustin Medical Eden Prairie, MN, USA).
According to our standard for induction of anaesthesia, patients received oxygen via a facemask. A bolus dose of propofol (1.5 mg kg−1 bodyweight), a continuous infusion of remifentanil (1.0 mg kg−1 min−1 for 1 min, followed by 0.1 mg kg−1 min−1), and vecuronium (0.1 mgkg−1) to facilitate endotracheal intubation were given. After endotracheal intubation, the continuous infusion of remifentanil was terminated and controlled ventilation of the lungs was established (Cato, Dräger, Germany; oxygen/air, FiO2 0.30, fresh gas flow 9 L min−1). For maintenance of anaesthesia, we used either isoflurane (group 1) or sevoflurane (group 2) as a single agent anaesthetic. All patients were kept normothermic (36-37°C) and normocapnic (PaCO2: 4.7-6kPa). Before anaesthesia induction, patients received 1500 mL of Ringer's solution as standard practice. When the mean arterial pressure (MAP) was lower than 50 mmHg, 0.02 mg phenylephrine as a bolus dose was administered . At a heart rate of less than 45 beats min−1, we administered 0.2 mg glycopyrrolate. If these interventions were necessary, haemodynamics were allowed to stabilize for 5 min before measurements were obtained. The following parameters were recorded: SBFv, CBFv, MAP, heart rate, PaCO2, oxygen saturation (SPO2), haematocrit, and body temperature.
Baseline measurements were recorded in the awake patient and repeated 5 min after reaching a steady state of inspiratory and end-expiratory concentration of 0.75, 1.00, and 1.25 MAC of either volatile anaesthetic determined by the gas detecting system of the Cato anaesthesia machine . Yasuda considers 5 min as sufficient for tissue equilibration . Therefore, we considered 5 min of constant inspiratory and end-expiratory levels as a steady state.
The mean CBFv was measured at the main trunk of the middle cerebral artery (MCA) by transcranial Doppler sonography at a depth of 50-60 mm via the temporal window (2-MHz Probe, Multi Dop Unit, Hitachi, Japan) . The probe was fixed in position by a specially designed frame throughout the study period. The mean SBFv was determined in the aorta in the five-chamber view by transthoracic insonation with a pulse wave Doppler at the depth of the aortic valve (3.5/2.7-MHz Probe, 1500 Sonos, Hewlett Packard, Palo Alto, CA, USA) [17,18]. We aimed carefully to keep the Doppler insonation angle constant. Placement of the patient and transducer position (apical 5-chamber view) was exactly the same for all measurements in one patient. Mathematical correction for deviation in the insonation angle to the axis of the left ventricular outflow tract, which could be problematic, was not necessary, because deviation of the angle in all measurements did not exceed 15-20°.
To calculate the relative changes in CBFv independently of relative changes in SBFv under isoflurane or sevoflurane, we used the cerebral-systemic blood flow velocity index (CSvl). CSvl was defined as the ratio of relative changes of CBFv under each concentration of isoflurane or sevoflurane vs. baseline (the awake patient) to the relative changes of SBFv under each concentration of isoflurane or sevoflurane vs. baseline. For instance, for 0.75 MAC of isoflurane, CSvl was defined as:
The unit of the CSvl is a percentage because a CSvl value of 100% indicates a 1:1 relationship between the relative changes in CBFv and SBFv. Values below 100% reflect that the decreasing effect on CBFv is more pronounced than the effect on SBFv, thus, indicating a direct reducing effect on CBFv independently of relative changes in SBFv.
Precisely, the study consists of two substudies, one quantifying the effects of isoflurane on CBFv and SBFv, and the other quantifying the sevoflurane effects. Variables of interest are described by mean and standard deviation and values of patients' characteristics in median and range. Hotelling's t-squared test was used to simultaneously assess multiple measurements taken within a patient . Potential dose-dependent effects were assessed by specifying and testing the appropriate contrast. All these tests were applied after a logarithmic transformation of the data. All reported P-values are the results of two-sided tests. P = 0.05 was considered statistically significant. The SAS (statistical analysis system) procedure GLM (SAS Institute Inc., Cary, NC, USA) was used to compute the multivariate statistical tests.
There was no difference in the patient's characteristics between the two groups (Table 1). MAP, heart rate, PaCO2, SPO2, body temperature, haematocrit, SBFv and CBFv of the two groups and the times of the measurements, respectively, are shown in Table 2. Compared with baseline, MAP demonstrated statistically significant lower values under isoflurane and sevoflurane, respectively (P= 0.0001, Hotelling's t-squared test). This effect was consistent at all three concentrations applied (0.75, 1.00, 1.25 MAC). Isoflurane and sevoflurane reduced SBFv and CBFv, respectively (Table 2, Figs 1, 2). At all three concentrations applied, CSvl values were statistically significant decreased vs. 100% (100% reflecting 1:1 relationship between relative changes of SBFv and CBFv) (Table 2, Fig. 3).
In the isoflurane group, we administered 0.02-0.06mg phenylephrine in three patients. In the sevoflurane, group we administered no phenylephrine. Three patients in the isoflurane group and one patient in the sevoflurane group received glycopyrrolate.
In addition, we observed a dose-dependent effect of isoflurane on CBFv that was not observed with sevoflurane. With increasing doses of isoflurane, CBFv decreased significantly vs. baseline (P=0.015; Hotelling's t-squared test) (Fig. 1).
CBFv can be measured easily and noninvasively by transcranial Doppler sonography . SBFv can be measured easily and noninvasively by transthoracic insonation of the aorta in the five-chamber view with a pulse wave Doppler [17,18]. It has been demonstrated that CBF and CBFv are changed under the influence of isoflurane and sevoflurane [5, 6, 7, 8,20,21]. It has not been investigated whether the reported relative changes of CBFv under the influence of volatile anaesthetics correlate with relative changes in SBFv. An index of intracranial to extracranial blood flow velocities is needed to exclude misinterpretation of CBFv values . In the presence of the same heart rate and a constant vessel diameter, SBFv and CBFv are comparable variables on one line of flow transmission. In our patients, heart rate decreased under the influence of isoflurane and sevoflurane compared with the awake patients. However, there is no difference in heart rate during simultaneous measurements of CBFv and SBFv. Doppler sonography cannot provide any information about the vessel diameter . However, our measurements of SBFv were taken in the aorta at the depth of the aortic valve. At this location, changes in vessel diameter do not occur . In addition, changes in the vessel diameter of the middle cerebral artery under the influence of volatile anaesthetics, changes in MAP, PaCO2 or the use of vasoactive drugs are not described [24,25].
CSvl is an index that reflects whether the relative changes of CBFv under volatile anaesthetics are independent of relative changes of SBFv. Our results clearly demonstrate that isoflurane and sevoflurane as single agent anaesthetics reduce SBFv and CBFv. In our study we observed a greater reduction of CBFv than of SBFv (Figs 1 and 2). CSvl values less than 100% indicate a direct decreasing effect of isoflurane and sevoflurane on CBFv, independently of SBFv (Fig. 3). Our MAP values showed a statistically significant decrease under the influence of isoflurane and sevoflurane compared with the awake patient. However, during preserved autoregulation, changed MAP values do not result in relative changes of CBFv. Gupta and his colleagues and Cho and his colleagues have demonstrated that sevoflurane has no influence on cerebral autoregulation up to 1.5 MAC [8,26]. Summors and his colleagues observed at the concentration of 1.5 MAC of either sevoflurane or isoflurane that cerebral autoregulation is better preserved during sevoflurane anaesthesia in humans . Therefore, the reduced MAP values under the influence of either anaesthetic can not explain the observed reduction of CBFv values.
Cho and his colleagues investigated the influence of sevoflurane on CBFv as a single agent anaesthetic vs. the awake patient . Without N2O, Cho's group found a reducing effect on CBFv . This is supported by our data. In our patients, sevoflurane reduces CBFv compared with the awake patient. Heath and his colleagues reported reduced brain oxygen consumption without effect on CBFv under the influence of large dose sevoflurane during propofol anaesthesia . When the cerebral metabolic rate is already depressed, sevoflurane increases CBF by vasodilation. As a single agent anaesthetic, sevoflurane decreases the cerebral metabolic rate of oxygen (CMRO2) and CBF . This theory is supported by our findings, because the reduction of CBFv under isoflurane and sevoflurane as single agent anaesthetics may be due to a decreased CMRO2 at all three concentrations. Matta and his colleagues found a direct cerebral vasodilator effect of isoflurane and sevoflurane [5,7]. Isoflurane and sevoflurane led to a dose-related increase of CBFv in the presence of a propofol-induced isoelectric EEG [5,7]. The effect of sevoflurane was less than that of isoflurane . These effects stand in contrast to our findings. However, our study protocol used isoflurane and sevoflurane as single agent anaesthetics. In addition, our baseline measurements were taken in the awake patients and not during anaesthesia. Our findings are supported by the fact that at a concentration between 1.0 and 2.0 MAC isoflurane reduces the CMRO2 and leads via coupling to an indirect vasoconstriction .
Kuroda and his colleagues investigated the effects of prolonged anaesthesia under isoflurane and sevoflurane on CBFv . In their study, CBFv did not exhibit decay over time and a dose-dependent change was not observed. Furthermore, baseline measurements in the awake patient were not taken. In our patients, volatile anaesthetics decreased CBFv vs. the awake patient. In addition, we found a dose-dependent reduction of CBFv under isoflurane, which stands in contrast to previously published data .
In conclusion, compared with the awake patient, isoflurane and sevoflurane as single agent anaesthetics reduce CBFv and SBFv, respectively. However, our results demonstrate that under the influence of isoflurane and sevoflurane, there is a direct effect on CBFv, independently of SBFv.
1 Werner C, Kochs E, Hoffmann WE. Cerebral blood flow and metabolism. In: Albin MS, ed. Textbook of Neuroanesthesia with Neurosurgical and Neuroscience Perspectives.
New York, USA: McGraw-Hill, 1997: 21-59.
2 Kirkham FJ, Padayachee TS, Parsons S, Seargeant LS, House FR, Gosling RG. Transcranial
measurement of blood velocities in the basal cerebral arteries using pulsed doppler
ultrasound: Velocity as an index of flow. Ultrasound Med Biol
3 Bishop CCR, Powell S, Rutt D, Browse NL. Transcranial doppler
measurements of middle cerebral artery blood flow velocity: a validation study. Stroke
4 Kochs E, Hoffman WE, Werner C, Albrecht RF, Schulte am Esch J. Cerebral blood flow velocity
in relation to cerebral blood flow, cerebral metabolic rate for oxygen, and electroencephalogram analysis during isoflurane
anesthesia in dogs. Anesth Analg
5 Matta BF, Mayberg TS, Lam AM. Direct cerebrovasodilatatory effects of halothane, isoflurane
, and desflurane during propofol-induced isoelectric electroencephalogram in humans. Anesthesiology
6 Heath KJ, Gupta S, Matta BF. The effects of sevoflurane
on cerebral hemodynamics during propofol anaesthesia. Anesth Analg
7 Matta BF, Heath KJ, Tipping K, Tipping K, Summors A. Direct vasodilatory effects of sevoflurane
8 Cho S, Fujigaki T, Uchiyama Y, Fukusaki M, Shibata O, Sumikawa K. Effects of sevoflurane
with and without nitrous oxide on human cerebral circulation. Anesthesiology
9 Malan TP, DiNardo JA, Isner RJ et al. Cardiovascular
effects of sevoflurane
compared with those of isoflurane
in volunteers. Anesthesiology
10 Bouma GJ, Muizelaar JP. Relationship between cardiac output and cerebral blood flow in patients with intact and with impaired autoregulation. J Neurosurg
11 Davis DH, Sundt TM Jr. Relationship of cerebral blood flow to cariac output, mean arterial blood pressure, blood volume, and alpha and beta blockade in cats. J Neurosurg
12 Levy ML, Rabb CH, Zelman V, Giannotta SL. Cardiac performance enhancement from dobutamine in patients refractory to hypervolemic therapy for cerebral vasospasm. J Neurosurg
13 Schuhmann MU, Suhr DF, v. Gösseln HH, Brauer A, Jantzen JP, Samii M. Local brain surface temperature compared to temperature measured at standard extracranial monitoring sites during posterior fossa surgery. J Neurosurg Anesth
14 Strebel SP, Kindler C, Bissonnette B, Tschalèr G, Deanovic D. The impact of systemic vasoconstrictors on the cerebral circulation of anesthetized patients. Anesthesiology
15 Yasuda N, Targ AG, Eger El II. Solubility of I-653, sevoflurane
, and halothane in human tissues. Anesth Analg
16 Aaslid R, Markwalder TM, Nornes H. Noninvasive transcranial Doppler
ultrasound recording of flow velocity in basal cerebral arteries. J Neurosurg
17 Lewis JF, Kuo LC, Nelson JG, Limacher MC, Quinones MA. Pulsed Doppler
echocardiographic determination of stroke Volume and cardiac output: clinical validation of two new methods using the apical window. Circulation
18 Gardin JM, Dabestani A, Matin K, Allfie A, Russell D, Henry WL. Reproducibility of Doppler
aortic blood flow measurements: studies on intraobserver, interobserver and day-to-day variability in normal subjects. Am J Cardiol
19 Pillai KCS. Hotelling's t
-squared. In: Kotz S, Johnson NL, eds. Encyclopedia of Statistical Sciences,
Vol. 3. New York, USA: Wiley, 1983: 669-673.
20 Kuroda Y, Murakami M, Tsuruta J, Murakawa T, Sakabe T. Preservation of the ratio of cerebral blood flow/metabolic rate of oxygen during prolonged anesthesia with isoflurane
, and halothane in humans. Anesthesiology
21 Kuroda Y, Murakami M, Tsuruta J, Murakawa T, Sakabe T. Blood flow velocity of middle cerebral artery during prolonged anaesthesia with halothane, isoflurane
, and sevoflurane
in humans. Anesthesiology
22 Lindegaard KF, Nornes H, Bakke J, Sorteberg W, Nakstad P. Cerebral vasospasm diagnosis by means of angiography and blood velocity measurements. Acta Neurochir
23 Waymen AE. Principles and Practice of Echocardiography,
2nd edn. Philadelphia, USA: Lea & Febiger, 1994: 962-977.
24 Matta BF, Lam AM. Isoflurane
and desflurane do not dilate the middle cerebral artery appreciably. Br J Anaesth
25 Giller CA, Bowman G, Dyer H, Mootz L, Krippner W. Cerebral arterial diameters during changes in blood pressure and carbon dioxide during craniotomy. Neurosurg
26 Gupta S, Heath K, Matta BF. Effects of incremental doses of sevoflurane
on cerebral pressure autoregulation in humans. Br J Anaesth
27 Summors AC, Gupta AK, Matta BF. Dynamic cerebral autoregulation during sevoflurane
anesthesia: a comparison with isoflurane
. Anesth Analg
28 Newberg LA, Milde JH, Michenfelder JD. The cerebral metabolic effects of isoflurane
at and above concentrations that suppress cortical electrical activity. Anesthesiology